A critical area in the investigation of gender differences in cocaine dependence is differences in factors influencing initiation, maintenance and relapse to drug use. Human laboratory studies indicate that both cocaine-related cues and negative emotional stimuli can elicit craving in cocaine-dependent individuals. There is some evidence to suggest that this effect may be more robust in women as compared to men. Animal studies have clearly demonstrated that exposure to stress facilitates both the initiation and reinstatement of substance use in previously dependent animals. The hypothalamic-pituitary-adrenal (HPA) axis, one of the most important hormonal systems involved in the stress response, is likely to be an important mediator of stress-facilitated drug self-ad ministration. Of particular relevance to this proposal, there are important gender differences in the response of the HPA axis to stress. Preliminary data from our group suggest gender differences in the biologic and subjective response to these different types of stressors. In this proposed study, we plan to build upon these intriguing findings. Specifically HPA axis (e.g., ACTH, cortisol), physiologic (e.g., HR, GSR) and subjective response to the presentation of cocaine-related cues and negative affect-inducing cues will be compared in cocainedependent men, women and matched control groups without cocaine dependence. A CRH stimulation test will also be performed. Following the test procedures, individuals will return for a follow-up visit at one week and one month to assess the amount and subjective attributions of drug use. In summary, this project is designed to build upon our ongoing research in the area of stress reactivity and substance use disorders. Specifically, this study will complement Project 1, which focuses on gender differences in animal models of reinstatement and will focus on gender differences in response to differing stimuli associated with relapse. Exploration of potential neurobiologic underpinnings of gender differences in precipitants relapse to drug use can have important implications for prevention and treatment.